PROJECT SUMMARY The DIAN-TU was formed to design and manage interventional therapeutic trials and find a treatment that provides cognitive benefit for those certain to develop autosomal dominant AD (ADAD). The DIAN-TU trial platform is now fully operational in 6 countries, 24 sites, 3 languages with ~100% completion of all assessments and ~3% attrition, and has completed enrollment in November 2015 for the first two drugs. Initial funding for the DIAN-TU trial platform established the infrastructure and operations for executing clinical trials in ADAD and acknowledged the need for evolution within this platform. The DIAN-TU Next Generation Prevention Trial will add a new drug arm to the DIAN-TU trial platform and implement key design changes that allow the platform to test additional drugs with diverse mechanisms of action more quickly. Significant innovations and specific aims include implementation of: (1) a planned cognitive run-in period prior to drug administration to provide greater power to detect drug effects, (2) self- administered cognitive testing, (3) pre-defined dose escalation algorithm to safely maximize target engagement, (4) four plus year cognitive endpoint adaptive trial design for asymptomatic subjects that includes both early biomarker and later cognitive interims to inform early efficacy or futility, and maximize power in a limited study population, (5) novel imaging (e.g. Tau PET and MRI) and cerebrospinal fluid (CSF) measures, and (6) ADAD Disease Progression Model (DPM) to detect changes in cognition earlier. These innovative approaches promise to accelerate identification of effective drugs for prevention and treatment of AD. diffusion basis spectrum imaging Many disease modifying therapies currently in development target A?, which is believed to be the initiator and earliest change in the AD process. These A? therapies may be most beneficial in the ADAD population and earlier in the disease to delay the onset of dementia. A fundamental and unresolved question is which target will provide the best cognitive response. The NexGen trial design is a multi-center, double blind, randomized, pooled placebo-controlled, four plus year cognitive composite endpoint registration study of a potential disease modifying therapy in 204 individuals at risk for or with dominantly inherited AD. The primary aim of this study will test the ability of a beta secretase inhibitor (BACEi) to prevent or slow cognitive decline in 100 asymptomatic (CDR 0) ADAD mutation carriers in the range of -15 to +10 years with respect to estimated age of symptom onset. A secondary aim of the study is to slow cognitive decline and progression in 140 CDR ?1 mutation carrier subjects. Subjects will receive either drug or placebo with 3:1 randomization for an average of 5.1 years to determine clinical benefit of the primary outcome of the DIAN-TU cognitive composite and secondary outcomes including multiple cognitive measures and fluid and imaging biomarkers.